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Why do Clarithromycin and Azithromycin Cause Less GI Side Effects than Erythromycin?

Summary:

  • GI toxicity is the most common side effect of erythromycin therapy.
  • In the acidic environment of the stomach, erythromycin is degraded to a hemiketal intermediate that serves as a motilin-receptor agonist, which stimulates a G-protein coupled pathway in smooth muscle cells of the GI tract leading to contractions.
  • The structural configurations of clarithromycin and azithromycin provide improved acid stability as compared to erythromycin, which results in fewer hemiketal intermediates being formed and thus, less GI effects. 

Author: Sarah White, PharmD
Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors: Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed:
October 2015

Explanation

  • Even though azithromycin is structurally different, the macrolide antibiotic drug class is traditionally known to include erythromycin, clarithromycin and azithromycin.   Compared to each other they do differ in a few areas that include side effect profiles, pharmacokinetic profiles, the potential to cause clinically relevant drug interactions, and indications or uses in clinical practice.  As it relates to the differences in side effect profiles, erythromycin is known to cause more gastrointestinal (GI) side effects as compared to clarithromycin and azithromycin. 

    The erythromycin molecule is comprised of a 14-membered lactone ring with two deoxy sugar groups (see figure below).1,2  The most common side effects of erythromycin therapy are gastrointestinal (GI) in nature and consist of diarrhea, nausea, vomiting and abdominal cramping.3  Erythromycin has poor stability in acidic environments and is rapidly degraded into intermediate metabolites after oral administration.3  One of these metabolites, 8,9-anhydro-6,9-hemiketal intermediate, serves as a motilin-receptor agonist, which is known to increase peristalsis and cause many of the common GI side effects.

                            

    Clarithromycin and azithromycin are synthetic analogs of erythromycin, developed in the 1990s in an effort to improve the adverse effect profile of macrolide antibiotics.  Clarithromycin contains a methylated hydroxyl group at position 6 of the prototype erythromycin molecule, while azithromycin consists of a 15-membered ring with a methyl-substituted nitrogen in place of the carbonyl group (see figures below).  The structural configurations of clarithromycin and azithromycin provide improved acid stability.1-3,7  As a result, fewer hemiketal intermediates are formed and GI effects tend to be less pronounced with these agents.3 

    References:

    1. MacDougall C. Chapter 55. Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011.
    2. Deck DH, Winston LG, Winston LG. Chapter 44. Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12nd ed. New York: McGraw-Hill; 2012. 
    3. Zuckerman JM, Qamar F, Bono BR. Macrolides, ketolides, and glycylcyclines: azithromycin, clarithromycin, telithromycin, tigecycline. Infect Dis Clin North Am. 2009 Dec;23(4):997-1026.  
    4. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005 Oct;17(5):643-53. 
    5. Abu-Gharbieh E, Vasina V, Poluzzi E, De Ponti F. Antibacterial macrolides: a drug class with a complex pharmacological profile. Pharmacol Res. 2004 Sep;50(3):211-22. 
    6. Sharkey KA, Wallace JL. Chapter 46. Treatment of Disorders of Bowel Motility and Water Flux; Anti-Emetics; Agents Used in Biliary and Pancreatic Disease. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. Accessed May 13, 2013. 
    7. Blondeau JM. The evolution and role of macrolides in infectious diseases. Expert Opin Pharmacother. 2002 Aug;3(8):1131-51.

MESH Terms & Keywords

  • Clarithromycin, Azithromycin, Macrolide Antibiotics, GI Side Effects, Motilin, Erythromycin